title: Synthesis of C (6)-epimer derivatives of diacetoxy acetal derivative of santonin and their inducing effects on HL-60 leukemia cell differentiation.
abstract: Induction of differentiation is a new and promising approach to leukemia therapy, well illustrated by the treatment of acute promyelocytic leukemia with 1,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] or all-trans retinoic acid (ATRA). Using combination of either 1,25-(OH)(2)D(3) or ATRA and chemotherapy, adverse effects 1,25-(OH)(2)D(3) or ATRA such as hypercalcemic effects have decreased, and long-term survival has improved. In a previous study, we demonstrated that santonin could be chemically modified into a diacetoxy acetal derivative of santonin with strong differentiation-inducing activity. In this study, we further synthesized C(6)-epimer derivatives of diacetoxy acetal derivative of santonin and tested their effects on HL-60 cell differentiation. Some of the C(6)-epimer derivatives themselves induced increases in cell differentiation. Especially, (11S)-3,3-(ethylenedioxy) eudesmano-13-ol-6β-acetate (7) was demonstrated to induce differentiation with larger than 80% of the cells attaining a differentiated phenotype. Importantly, 7 strongly enhanced differentiation of HL-60 cells in a dose-dependent manner when combined with either low doses of 1,25-(OH)(2)D(3) or ATRA. The ability to enhance the differentiation potential of 1,25-(OH)(2)D(3) or ATRA by 7 may improve outcomes in the therapy of acute promyelocytic leukemia.
authors.affiliation: School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
authors.forename: Sin Ho
authors.initials: SH
authors.lastname: Kweon
authors.forename: Keun Tae
authors.initials: KT
authors.lastname: Kim
authors.forename: Joon
authors.initials: J
authors.lastname: Hee Hong
authors.forename: Tae Sung
authors.initials: TS
authors.lastname: Kim
authors.forename: Bo Gil
authors.initials: BG
authors.lastname: Choi
mesh_terms: D000080:Acetals / Q000032:analysis / Q000138:chemical synthesis* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000032:analysis / Q000138:chemical synthesis* / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D012500:Santonin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D014807:Vitamin D / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C511609:3,3-(ethylenedioxy)-eudesmano-13,6-diacetate; D000080:Acetals; D000970:Antineoplastic Agents; D014807:Vitamin D; D012500:Santonin; D014212:Tretinoin; C097949:1,25-dihydroxyvitamin D